Study Suggests Protein May Be Early Warning For Ovarian Cancer

The Penn State team of scientists led by principalinvestigator Kathleen M. Mulder, Ph.D., professor of pharmacology, andworking in conjunction with a researcher from the Center for CancerResearch, National Cancer Institute in Bethesda, Md., studied "km23," aprotein that helps to direct protein traffic in the cell. Mulder's teamhas found that at least 42 percent of ovarian cancer patient tumortissues have alterations in km23. No similar alterations in km23 weredetectable in normal human tissues, suggesting that it may be both adiagnostic indicator for the development of ovarian cancer and apossible target for cancer therapies. "While only close to half ofovarian cancer patients may have defects in km23, our results are stillhighly significant because there is no clinically useful screening testavailable for detection of ovarian cancer," said Mulder.

Additionalstudies are under way to continue the analyses of km23 abnormalities inspecimens from women with ovarian cancer, and to determine whetherdifferent km23 alterations exist in other solid tumors, such as breastand colon cancer. "The next step is to develop a screening test forearly detection of the km23 alterations in the blood of ovarian cancerpatients," Mulder said. In addition, studies are under way to developdrugs that would target km23 and override the defects caused by thekm23 alterations in the cancer cells. "The plan is to be able to usethe screening test to identify those patients who would benefit fromthe anti-cancer drugs we will be developing using km23 as the target,"Mulder said. "In the pharmaceutical industry, this is often referred toas 'personalized medicine,' meaning that each patient can be checkedfor alterations in specific genes and their treatment targeted for thealterations specific to their cancer."

Epithelial ovarian canceris often diagnosed at an advanced stage and accounts for more than16,000 deaths annually. Despite advances in surgical techniques andchemotherapy, overall survival rates for women with ovarian cancer havenot improved significantly because of late detection, often after thedisease has already spread to remote organs. The identification of apotential early warning signal and a possible therapeutic target forthe disease could lead to improved survival rates.

km23 isresponsible, in part, for the movement of cellular proteins alongmicrotubules, the "highways" of the cell. The cellular proteins, or"cargo," are actually driven along the microtubules by "motors" in thecell. km3 helps to connect the right cargo to the motor so that thecargo can reach its appropriate destination.

In a previous study,Mulder and her team found that the process is initiated by the bindingof a factor called "TGFß" to receptors on the cell's surface. This, inturn, sends a signal to km23 telling it to attach to the motor and pickup the cargo. When km23 is altered, the cargo doesn't reach the correctdestination in the cell. As a result, a traffic jam occurs, whichcauses chaos in the cell.

This latest study, titled "A TGFßreceptor-interacting protein frequently mutated in human ovariancancer," was published in the Aug. 1 issue of Cancer Research,http://cancerres.aacrjournals.org/.

The initiator of the journey, TGFß, has been the focus of Mulder's research program since 1988.

"TGFßis a critical regulator of cell growth and is present throughout thebody," she said. "It is already known to play an important role insuppressing the growth of epithelial cells, the type of cell that givesrise to solid tumors. When the appropriate signals are not sent byTGFß, the growth of epithelial cells will not be controlled and a solidtumor can form. The alterations in km23 appear to disrupt some of thenormal signals sent by TGFß."

"The km23 alterations we haveidentified in human ovarian tumor tissues, described in our recentreport, might also be used as prognostic indicators to help physiciansdecide on the most appropriate treatment for each patient," Mulder said.

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Thisresearch was funded by the National Cancer Institute of the NationalInstitutes of Health, and in part, by the U.S. Department of Defense.